Life science research has developed into an extremely important area of modern scientific inquiry. Such research is used for example to discover new drugs, to investigate and sequence DNA and other genetic material, and to culture tissues for disease diagnosis to name a few of many areas of concentration.
Laboratory personnel in such laboratory environments are often required to accurately and safely handle and dispense relative small quantities of fluids. For example, a lab technician may prepare an aqueous (water-based) solution of cell nutrient that must be distributed in accurate quantities among a relatively large number of different containers (e.g., small culture tubes, test tubes, microcentifuge tubes, etc.). Often, the technician is faced with a need to dispense precise amounts of such a prepared solution into a large number of containers in multiple trays. See FIG. 1. To provide accurate results, the liquid must be dispensed in relatively accurate and consistent amounts (e.g., better than 5% accuracy).
One common way of dispensing relatively small quantities of liquid is to use a narrow glass or plastic tube called a pipette. Most of us have, at one time or another, experimented with dispensing liquid using a drinking straw. Think of a drinking straw inserted into a glass of liquid so the liquid partially fills the straw. If you seal the uppermost open end of the drinking straw with your finger or thumb, you will be able to remove the drinking straw from the glass of liquid while still retaining the liquid within the straw. The liquid column remains in the straw because a vacuum is created at the top of the liquid column due to the force of gravity pulling the liquid down toward the bottom of the straw. The outside atmospheric pressure presses against the liquid at the open bottom end of the straw to maintain the liquid within the straw. When you release your finger or thumb to open up the drinking straw's top end, the vacuum is filled by atmospheric pressure rushing in to the top end of the straw and the liquid immediately runs out of the straw's bottom end.
Of course, laboratory researchers generally do not use drinking straws to handle and dispense liquids, but they use something quite similar in principle—a narrow disposable glass or plastic tube pipette. Such pipettes come in various standard sizes such as 5 ml, 10 ml, 20 ml, 50 ml, etc. Typically, the pipette has graduations so that the laboratory researcher can read the level of liquid in the tube as it is being dispensed.
Several decades ago, it was common for laboratory researchers to apply mouth suction to the top end of the pipette to suck or “aspirate” a column of liquid into the tube—thus allowing the level of liquid in the pipette to rise above the liquid level in container from which it was being drawn. However, this was relatively time consuming and could be dangerous if the fluids being dispensed were hazardous to health. In addition, mouth suction techniques were not conducive to a sterile environment or the exacting procedures required for genome sequencing and tissue culturing. Accordingly, there came a time several decades ago when various companies began developing “pipetter” handheld devices that accepted common disposable or non-disposable pipettes and which would supply powered suction and positive pressure to the open uppermost end of the pipette to draw up and release liquids. A leader in this development effort was Drummond Scientific Co. of Broomall Pa.—the owner of this patent. Drummond's vanguard development efforts resulted in a number of issued United States patents including for example U.S. Pat. Nos. 3,834,240; 3,963,061; 4,461,328; 4,624,147; 5,104,625; 5,214,968; 5,294,405; 5,616,871; and U.S. Pat. No. 5,090,255.
Drummond Scientific's associated pipetter products have been highly successful in the marketplace—making Drummond a leader in the pipetter field. For example, Drummond was one of the first if not the first to develop a practical, economical handheld gun-shaped portable pipetter device that allowed a laboratory technician or other user to depress variable-stroke push buttons to vary the amount of suction applied to the uppermost end of a pipette. To dispense liquid using this type of device, the user simply attaches a pipette to the gun-shaped handle and places the bottom end of the pipette into a liquid to be dispensed. Depressing the top button with a forefinger causes the pipetter to apply suction that draws liquid up into the pipette tube. This power suction allows the pipette to draw a liquid level higher than the level in the liquid reservoir sourcing the liquid being drawn. Upon attaining a desired column height, the user releases the top button to seal the top end of the pipette tube and thus maintain the liquid column level in the tube. The user may then lift the pipette out of the initial fluid reservoir and place it into or above the container into which the fluid is to be dispensed.
The user dispenses the fluid by depressing a down button while watching the descending column height relative to the graduations marked on the pipette tube. The user releases the down button when the desired quantity has been dispensed. The user may dispense additional quantities, or “aliquots,” into additional receptacles until most or all of the fluid within the pipette tube has been dispensed. The entire process may be repeated multiple times. Power dispensing reduces dispensing time and can also help to mix the fluid with contents already present in the container into which the fluid is being dispensed.
In this type of device marketed by Drummond in the past, the up and down buttons are coupled to needle or other valves having variable apertures. This allows the user to control the speed of aspiration or dispensing by varying the amount of pressure he or she applies to the up and down buttons respectively. A light touch on the button results in slower aspiration or dispensing, while a more firm depression increases the rate at which the fluid is drawn up or dispensed from the pipette tube. In come contexts, users may wish to dispense with some force so the dispensing agitates and mixes the resulting solution in the receptacle into which the liquid is being dispensed. In other cases, the user may be very concerned about dispensing nearly exact quantities and so will use a slower dispensing speed while more carefully watching the fluid column height relative to visual graduations on the pipette tube.
The Drummond products described above have worked extremely well over the years in a wide variety of laboratory contexts and have therefore been very successful. However, there are some instances when it would be desirable to reduce the amount of skill and potential tedium required to accurately dispense a large number of nearly identical quantities of fluid aliquots into a number of receptacles. In the industry, there has been a long felt but unsolved need for a relatively inexpensive, handheld or other dispensing apparatus that can be coupled to a standard laboratory pipette and which can be programmed to accurately and repetitively dispense a precise amount of liquid.
In the early 1990s, Drummond Scientific worked to solve this problem by developing an automatic pipetter based on a precision syringe and piston. See U.S. Pat. No. 5,090,255. A microcontroller operated a motor which in turn was mechanically coupled to the piston via a threaded shaft. Moving the piston out of the syringe by a precise displacement created suction which drew liquid into the pipette. Plunging the piston into the syringe a precise displacement caused a precise corresponding quantity of fluid to be dispensed from the pipette. The amount the piston was displaced precisely controlled the amount of fluid being “aspirated” or dispensed. This design was quite successful in automatically repetitively dispensing programmable amounts of liquid with a high degree of accuracy and precision. However, a disadvantage was the relatively high cost and complexity of the positive-displacement syringe-and-plunger arrangement. Positive-displacement-type devices are often handicapped by slower dispensing speeds and total column-height volumes that are limited to the plunger displacement volume. This means that handheld devices are generally limited due to the portability issue. It would therefore be highly desirable to provide automatic dispensing functionality in the context of a less expensive, more portable, all-electronic design not subject to these limitations.
One of the challenges to providing an improved automatic dispensing design relates to the number of variables that computer control needs to take into account in the context of a so-called “non-contacting” open-loop system to provide a requisite degree of accurate dispensing. One might initially think, for example, that it would be relatively straightforward to use a liquid flow sensor to accurately measure the amount of liquid being dispensed in the context of a conventional closed-loop control system. However, it must be remembered that many laboratory procedures require that no part of the dispensing apparatus other than the disposable or non-disposable, sterilized pipette come into contact with the fluid being dispensed. It is therefore undesirable or impossible in many contexts to use a flow sensor in contact with the fluid being dispensed to monitor fluid flow amount.
We have now discovered a way to control a relatively simple, inexpensive pipetter or other fluid dispenser to provide precision, repetitive, automatic dispensing of programmable fluid quantities. One exemplary, illustrative implementation of our technique mathematically models the pneumatic system of the dispensing apparatus—including the removable pipette tube—with a non-linear model. There are various methods by which the pipette and pipetter systems can be modeled. One exemplary illustrative non-limiting arrangement is aspirating to a specific and consistent column height, and dispensing in fixed time increments. Through such non-linear mathematical modeling, a computing element such as for example a relatively inexpensive microprocessor can be used to accurately control valve aperture and/or pump power to achieve relatively high precision of dispensing quantity in the context of an inexpensive handheld gun shaped or other pipetter or other dispensing system.
Non-limiting, exemplary illustrative advantages of our approach include for example: avoids need for positive displacement type syringe-piston arrangements and/or expensive, complicated peristaltic or other pumps                mathematically and physically models non-linear system to provide a high degree of accuracy and precision        open-loop system—avoids need for closed-loop control        relatively light weight        inexpensive, rugged design        simple, reliable mechanics        easy to operate, intuitive operation        precise repetitive automatic dispensing of aliquots        relatively quiet operation        can correct for a variety of factors including, for example, dispensing at different angles, different pipette diameters, changing pump motor efficiency, different fluid viscosities, other        drip prevention or elimination        users not required to constantly pay attention to graduations on pipette tube during automatic dispensing        electronic controller/substantially all electronic design        programmable dispensing amount        electronic valve and pressure sensor        no contact/no fluid sensing orifice        pressure and vacuum operation        handheld (e.g., gun shaped)        controllable automatic dispensing rate and quantity        accommodates differently sized pipettes in some implementations        high accuracy (e.g., 1% or greater)        high repeatability        relativistic in operation        self-powered        intuitive graphical display and associated user interface        vane type electronic pump in some implementations        reversible orifice valve in some implementations        reversible pump motor in some implementations        plural pressure sensors in some implementations        look-up table in some implementations        no pressure sensors in some implementations        combined high-speed multiple decrements to achieve single larger volume aliquot dispensings        blocked filter detector        substantial increase in speed and efficiency of dispensing, reducing lab labor expenses and time        use of large volume pipettes to accurately dispense very small aliquots, reducing aspirations and decreasing the quantity of pipettes required and/or changed        automatic aspiration to preset column heights        automatic aspiration when pipette tip is inserted in liquid look-up table or formula-based dispensing single calibration for all pipette sizes make use of any volume pipette, including 100 ml or greater, without being negatively impacted in dispensing accuracy or precision.        
In one non-limiting, exemplary illustrative implementation, a pressure calibration technique is used to establish a base line. In one exemplary illustrative implementation, two column height pressure readings are taken: one for a given column height near the top of the pipette and another for a given column height near the bottom of the pipette. These pressure readings are used to calculate constants for a mathematical equation that outputs valve open time and/or pump power for dispensing a desired quantity of liquid. During active dispensing, column height pressure is continually monitored and used to calculate or look up the corresponding valve and/or pump control parameters. Accuracies better than 1% have been achieved.